Substances active against microorganisms have many beneficial uses. These uses are in fields such as human health care, veterinary science, and animal husbandry. Antimicrobial agents can have many desirable effects such as preventing or curing disease and promoting the growth of animals.
New antimicrobial agents are needed for several reasons; these include intolerance of the subject to be treated to known antimicrobials, and the development of strains resistant to known antimicrobials. Therefore, characterization of any previously known microorganisms which produce new antimicrobial agents is highly desirable.
Nerve growth factor (NGF) is a protein known to be essential for the development and maintenance of certain sympathetic and sensory neurons in the peripheral nervous system (Thoenen, et al. Physiol. Rev. 60:1284-1335, 1980). Recent evidence also suggests important functions of NGF in the cholinergic neurons of the basal forebrain in the central nervous system (Whittemore, et al. Brain Res. Rev. 12:439-464, 1987). It has further been reported that in aged rodents, impairments in learning and memory are related with age-dependent decline in the forebrain of cholinergic functions (Goelet, et al. Nature 322:419-422, 1986), and that the cholinergic neurons in the nucleus basalis magnocellularis, septal-diagonal band area and striatum undergo age-dependent atrophy (Schwartz et al. Ann. Rev. neurosci 10:459-476, 1987) Thus, as in Alzheimer-type dementia in man, degenerative changes of the forebrain cholinergic system may cause age-related cognitive impairments in rodents. It is known that the central cholinergic neurons in the septal-diagonal band area, nucleus basalis and striatum are sensitive to NGF (Eppler, et al. J. Cell Biol. 102:320-321, 1986). In fact, intraventricular injections or infusions of NGF in young adult rats have been shown to prevent retrograde neuronal cell death (Scholz, et al. Science 235:685-687, 1987) and promote behavioral recovery after damage to the septohippocampal connections (Weiss, et al. J. Neurophysiol. 42:791-803, 1979). NGF also has been reported to ameliorate cholinergic neuron atrophy and spatial memory impairment in aged rats (Fischer, et al Nature 329:65-68, 1987). PC12 pheochromocytoma cells, which are regarded as an important model system for study of adrenergic neuronal differentiation (Greene, et al. Proc. Natl. Acad. Sci. USA 73:2424-2428, 1976), respond to NGF, and differentiate into sympathetic neuron-like cells, exhibiting marked hypertrophy of the cell leading to extension of slender neurites which are piloted by well defined growth cones. Although several recent studies have indicated that protein kinase C is an important component of the NGF-sensitive phosphorylation system in PC 12 cells (Hama, et al. Proc. Natl. Acad. Sci. USA 83:2353-2357, 1986), NGF-associated biochemical pathways and their relationships to neurite outgrowth have not fully been elucidated. In search for potential factors which are able to modulate NGF synthesis or to mimic NGF (stimulate cell differentiation), several compounds have been reported which are summarized in the following table.
______________________________________ NGF Mimic Compounds Reported Compound Note Reference ______________________________________ Catecholamines NGF inducer Y. Furukawa, et al. J. Biol. Chem. 261 6039-6047, 1986 S. Furukawa, et al. Biochem. Biophys. Res. Commun. 147 1048-1054, 1987 Aminoalkylester NGF inducer S. Furukawa, et al. Japan derivs. Open-Laid Patent: 2-172955 Gangliosides NGF-like S. Tsuji, et al. J. Biochem. 94 303-306, 1983 Cuello, et al. Proc. Natl. Acad. Sci. 86 2056-2060, 1989 Wu, et al., J. Neurochem. 56 95-104, 1991 Tsuji, et al. J. Neurochem. 50 414-423, 1988 Sialyl compounds NGF-like Tsuji, et al. J. Neurochem. 50 414-423, 1988 Saponins Neuronotrophic Himi, et al. Chem. Pharm. activity Bull. 37 481-484, 1989 1,25-Dihydroxy- NGF inducer Wion, et al. J. Neurosci. vitamin D.sub.3 Res. 28 110-114, 1991 Adenosine Neuritogenesis Huffaker, et al. J. Cell inducer Physiol. 120 188-196 1984 Guroff, et al. J. Neurochem. 37 1431-1439, 1981 Staurosporine Differentiation Morioka, et al. Agric. Biol. inducer Chem. 49 1959-1963, 1985 Lactacystin Neuritogenesis Omura, et al. J. Antibiotics inducer 44 113-116, 1991 Peptide hormones NGF inducer Wion, et al. FEBS Lett. 189 37-41, 1985 Retinoic acid NGF inducer Wion, et al. Biochem. Biophys. Res. Commun. 149 510-514, 1987 Phorbol 12-myri- NGF inducer Wion, et al. FEBS Lett. 262 state 13-acetate 42-44, 1990 Dibutyryl-cyclic Neuritogenesis Prasad, et al. Cancer 36 1338 AMP inducer 1975 ______________________________________
Particularly, lactacystin is a microbial metabolite produced by a Streptomyces strain (Omura, et al. J. Antibiotics 44:113-116, 1991).
Methods for treating neurodegenerative diseases by administration of compounds which are able to modulate NGF synthesis or to mimic NGF by correlation with activity in the PC12 pheochromocytoma cell model systems are known in the art (see U.S. Pat. Nos. 5,075,305 and 5,098,902). Additionally, it has been clinically reported that intraperitoneal infusion of NGF supports adrenal medullary autografts in Parkinson's disease (Olsen, et al., Arch. Neurol. 48:373-381, 1991).
It would be highly desirable to identify new compounds which are useful in treating neurodegenerative disease such as Alzheimer's and dementia associated with Parkinson's disease.